Immunological and molecular features of the tumor microenvironment of long-term survivors of ovarian cancer
BACKGROUNDDespite an overall poor prognosis, about 15% of patients with advanced-stage tubo-ovarian high-grade serous carcinoma (HGSC) survive 10 or more years after standard treatment.METHODSWe evaluated the tumor microenvironment of this exceptional, understudied group using a large international cohort enriched for long-term survivors (LTS; 10+ years; n = 374) compared with mid-term (MTS; 5-7.99 years; n = 433) and short-term survivors (STS; 2-4.99 years; n = 416). Primary tumor samples were immunostained and scored for intraepithelial and intrastromal densities of 10 immune-cell subsets (including T cells, B cells, plasma cells, myeloid cells, PD-1+ cells, and PD-L1+ cells) and epithelial content.RESULTSPositive associations with LTS compared with STS were seen for 9 of 10 immune-cell subsets. In particular, the combination of intraepithelial CD8+ T cells and intrastromal B cells showed near 5-fold increased odds of LTS compared with STS. All of these associations were stronger in tumors with high epithelial content and/or the C4/Differentiated molecular subtype, despite immune-cell densities generally being higher in tumors with low epithelial content and/or the C2/Immunoreactive molecular subtype.CONCLUSIONThe tumor microenvironment of HGSC LTS is distinguished by the intersection of T and B cell coinfiltration, high epithelial content, and C4/differentiated molecular subtype, features which may inspire new approaches to immunotherapy.FUNDINGOvarian Cancer Research Program (OCRP) of the Congressionally Directed Medical Research Program (CDMRP), U.S. Department of Defense (DOD); American Cancer Society; BC Cancer Foundation; Canada's Networks of Centres of Excellence; Canadian Cancer Society; Canadian Institutes of Health Research; Cancer Councils of New South Wales, Victoria, Queensland, South Australia, and Tasmania, Cancer Foundation of Western Australia; Cancer Institute NSW; Cancer Research UK; Deutsche Forschungsgesellschaft; ELAN Funds of the University of Erlangen-Nuremberg; Fred C. and Katherine B. Andersen Foundation; Genome BC; German Cancer Research Center; German Federal Ministry of Education and Research, Programme of Clinical Biomedical Research; Instituto de Salud Carlos III; Mayo Foundation; Minnesota Ovarian Cancer Alliance; Ministerio de Economía y Competitividad; Medical Research Council (MRC); National Center for Advancing Translational Sciences; National Health and Medical Research Council of Australia (NHMRC); Ovarian Cancer Australia; Peter MacCallum Foundation; Sydney West Translational Cancer Research Centre; Terry Fox Research Institute; The Eve Appeal (The Oak Foundation); UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; University of Pittsburgh School of Medicine; U.S. National Cancer Institute of the National Institutes of Health; VGH & UBC Hospital Foundation; Victorian Cancer Agency.
Authors
Funding
Cancer Research UK Grant 10124University of Michigan Rogel Cancer Center Support Grant 2023-2028General Clinical Research CenterInflammation and Ovarian CancerGenes, Hormones & Environment in an Ovarian Cancer ModelGenetic Variation in the NF-kappaB Pathway and Ovarian Cancer EtiologyCancer Risk Assessment, Early Detection, and Interception Research ProgramCancer Biology Research ProgramSteroid Hormone Genes and Ovarian Cancer RiskProject 2: Next Generation TOP1 Inhibition for the Treatment of Ovarian CancerMulti-omic Predictive Markers for Ovarian Cancer Therapy Response and OutcomesEpidemiology of Ovarian Cancer:New HypothesesCollaborative Genetic Study of Ovarian Cancer RiskUCLA Clinical and Translational Science InstituteDana-Farber/Harvard Cancer Center Ovarian Cancer SPOREOVARIAN CANCER RISK AND SURVIVAL IN BRCA CARRIERSPathologyMedical Research Council Grant MC_UU_00004/01Relating Molecular Subgroups of Endometriosis-Associated Ovarian Cancers to Survival and RiskCancer Research UK Grant 10119UCLA Clinical and Translational Science InstituteU.S. Department of Defense Grant W81XWH-16-2-0010BC Cancer Foundation Grant NoneTerry Fox Research Institute Grant Project 1060Canadian Institutes of Health Research Grant 427647Canadian Cancer Society Grant 705904Canada’s Networks of Centres of Excellence Grant BioCanRxPathologyDeutsche Forschungsgesellschaft Grant HE 8699/1–1National Health and Medical Research Council of Australia Grant 1186505U.S. Army Medical Research and Materiel Command Ovarian Cancer Research Program Grant W81XWH-21-1-0401Victorian Cancer Agency Grant MCRF22018Canadian Institutes of Health Research Grant MOP-86727Medical Research and Materiel Command Grant DAMD17-01-1-0729National Health & Medical Research Council of Australia Grant 199600,400413,400281Cancer Council Queensland Grant noneCancer Council South Australia Grant noneCancer Council Tasmania Grant noenCancer Council Victoria Grant noneCancer Council New South Wales Grant noneCancer Foundation of Western Australia Grant 191,211,182Ovarian Cancer Australia Grant nonePeter MacCallum Foundation Grant noneUniversity of Erlangen-Nuremberg Grant noneCarlos III Health Institute Grant PI 12/01319Ministerio de Economía y Competitividad Grant SAF2012National Institutes of Health Grant R01-CA112523,R01-CA87538German Federal Ministry of Education and Research Grant noneProgramme of Clinical Biomedical Research Grant 01 GB 9401German Cancer Research Center Grant DKFZU.S. National Institutes of Health Grant R01-CA58598,N01-CN-55424,N01-PC-67001University of Pittsburgh School of Medicine Grant noneU.S. Department of Defense Grant DAMD17-02-1-0669,OC20085United States National Cancer Institute Grant R21-CA267050,K07-CA080668,R01-CA95023,MO1-RR000056American Cancer Society Early Detection Professorship Grant SIOP-06-258-01-COUNNational Center for Advancing Translational Sciences Grant UL1TR000124National Institutes of Health Grant R01-CA122443,P30-CA15083,P50-CA136393Mayo Foundation Grant noneMinnesota Ovarian Cancer Alliance Grant noneFred C. and Katherine B. Andersen Foundation Grant noneNational Institutes of Health Grant R01-CA54419,P50-CA105009U.S. Department of Defense Grant W81XWH-10-1-02802Cancer Research UK Grant C490/A10119,C490/A10124UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge Grant noneOak Foundation Grant MC_UU_00004/01Deutsche Forschungsgemeinschaft Grant noneCollaborative Research Center Grant 685BC Cancer Foundation Grant noneVGH & UBC Hospital Foundation Grant noneNational Health and Medical Research Council of Australia Grant ID 310670,ID 628903Cancer Institute NSW Grant 12/RIG/1-17,15/RIG/1-16Cancer Institute NSW Grant 15/TRC/1-01